NF-ΚB/JAK-STAT Signaling in Pediatric Metabolic and Inflammatory Disorders: Molecular Mechanisms Linking Chronic Inflammation to Insulin Resistance and Emerging Targeted Therapeutic Strategies

Abstract

Background: Chronic low-grade inflammation driven by the Nuclear Factor kappa-B (NF-κB) and Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathways is increasingly recognized as a molecular bridge linking pediatric inflammatory disorders to insulin resistance (IR). However, quantitative evidence from South Asian pediatric cohorts remains scarce. This study aimed to investigate the molecular mechanisms connecting NF-κB/JAK-STAT signaling to IR in pediatric patients with chronic inflammatory and metabolic disorders and to evaluate the implications for emerging targeted therapies.
Methods: A prospective, cross-sectional analytical study was conducted across three tertiary care hospitals in Karachi, Pakistan (January 2025–August 2026). The cohort comprised 400 pediatric patients (aged 5–18 years) diagnosed with juvenile idiopathic arthritis (JIA, n=145), pediatric inflammatory bowel disease (pIBD, n=110), or primary obesity with IR (n=145). Fasting serum levels of NF-κB (p65), JAK2, STAT3, and SOCS3 were quantified via ELISA. IR was assessed using HOMA-IR. Data normalization via log-transformation was applied to skewed biomarker distributions. Statistical analyses included Pearson's correlation and multiple linear regression.
Results: Overall, 67.0% of the cohort exhibited elevated HOMA-IR (>2.5), with the highest prevalence in the obesity subgroup (76.6%) and adolescents aged 15–18 years (81.0%). Age-stratified analysis revealed a progressive, significant increase in NF-κB, JAK2, STAT3, and HOMA-IR from childhood to adolescence (p<0.001). Strong positive correlations were observed between SOCS3 and HOMA-IR (r=0.65, p<0.001) and NF-κB and HOMA-IR (r=0.62, p<0.001). Multiple linear regression identified log(SOCS3) (standardized β=0.31, p<0.001) and log(NF-κB) (standardized β=0.28, p<0.001) as the strongest independent predictors of HOMA-IR (model R²=0.58, p<0.001).
Conclusion: NF-κB and SOCS3-mediated JAK-STAT signaling independently and significantly drive insulin resistance in pediatric inflammatory and metabolic disorders. These findings support a paradigm shift toward targeted pathway inhibitors—including selective JAK inhibitors and novel NF-κB modulators, as dual-purpose therapeutic strategies capable of simultaneously controlling inflammation and preserving metabolic homeostasis in pediatric populations.